1-(alpha-pyrryl)-2-amino ethanols



United States Patent 3,539,589 1-(u-PYRRYL)-2-AMINO ETHANOLS Uberto M. Teofino and Davide Della Bella, Milan, Italy, assignors to Whitefin Holding S.A., Lugano, Switzerland No Drawing. Filed May 8, 1967, Ser. No. 636,649

Claims priority, application Great Britain, May 17, 1966,

21,779/ 66 Int. Cl. C07d 27/22, 29/16, 87/22 US. Cl. 260-3265 4 Claims ABSTRACT OF THE DISCLOSURE Compounds acting on the central nervous system and on the peripheral nervous system, having the formula:

This invention relates to N,N-disubstituted pyrrylaminoethanols of the formula:

I R: R I

wherein R is an alkyl, aryl or arylalkyl group which may be substituted by one or more halogen atoms, alkyl, hydroxy, alkoxy, trifiuoromethyl, nitro, amino monoor dialkylamino radicals; R is an alkyl or cycloalkyl radical; R is an alkyl, or arylalkyl group, or taken together with R and the nitrogen atom to which they are attached, is a heterocyclic ring which may include a further hetero atom; and R is a hydrogen atom or an alkyl radical, and their salts with organic and inorganic acids and alkyl halides.

This invention relates to disubstituted arninoethanols or their physiologically tolerable salts with acids or alkyl halides in admixture or conjunction with a pharmaceutically acceptable carrier or diluent.

The disubstituted aminoethanols of this invention can be prepared according to this invention by reducing a compound of the formula:

V l i \N CO-CHN\ i R R 3,539,589 Patented Nov. 10, 1970 period of from 2 to 60 hours. This method is particularly useful for reducing the keto-group only when there are present in the molecule other groups which may be affected by hydrogenation.

The starting materials of the Formula II may be prepared according to the processes disclosed in our patent specification Ser. No. 636,643 of even date herewith.

The acid addition salts of the new compounds of this invention can be prepared in the usual manner, that is by reacting the disubstituted aminoethanols with either the stoichiometric amount of organic or inorganic acid in water or in a water-miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in a water-immiscible solvent, such as diethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are maleic, fumaric, benzoic, ascorbic, succinic, methanesulphonic, benzenesulphonic and hydroxy-benzoic acids. The preferred salts of this invention are salts of aromatic hydroxy-carboxylic acids as p.hydroxybenzoic, gentisic, gallic, protocatechuic, and B-resorcylic acid. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic and sulphuric acids. The quaternary ammonium salts of this invention can be prepared by reacting a disubstituted aminoethanol of the general Formula I with a lower alkyl halide, such as methyl bromide or methyl iodide.

The new compounds of this invention exhibit significant properties on the central or peripheral nervous system. Particularly marked are the sedative and analgesic efliects on the CNS. The analgesic activity has been tested in mice by the hot-plate test and by the stretching by injection of acetic acid. With regard to the latter test the ED values in mice of l-ot-(N-o-chlorobenzyl)-pyrryl-2- disec.butylaminoethanol are 0.7 mg./ g. subcutaneously and 1.5 mg./ 100 g. orally. By the oral route l-a-(N- o-chlorobenzyl)-pyrryl-2-disec.butylaminoethanol is three times more potent than codeine, nine times more potent than aminopyrine and twelve times more potent than acetylsalicyclic acid. The peak analgesia occurs in 60 minutes, but the effect is marked also four hours after drug administration.

The study of the sedative activity has been carried out by testing:

(a) The behavior of animals treated with the new compounds of this invention; reduction of motility and lessened reactivity were noted.

(b) The influence of the eifects of subhypnotic and hyp notic doses of barbiturates.

(c) The sedative effect on the cough centre previously excited by an ammoniacal aerosol in rat and by electrical stimulation of the superior laryngeal nerve in decerebrate cat. According to the last test the ED values are of from 8 to 20 mg./kg. in rat and from 5 to 10 mg./kg. intraperitoneally in cat.

The compounds of this invention have shown a very low toxicity: LD values higher than 100 mg./ kg. by the intraperitoneal route in mice; higher than 400 mg./ kg. by the oral route in mice and rat. A daily administration of 100 mg./kg. for three months is well tolerated in rats. The examination of the tissues following slaughter did not reveal evidence of pathological changes and the hematologic values found were unaffected.

The compounds of this invention can be administered orally, subcutaneously or intravenously in any pharmaceutical form suitable for these administration routes.

The following examples illustrate the invention.

3 EXAMPLE I 5.4 g. (0.022 mol) of 1-benzyl-2-dimethylaminoacetylpyrrole and 40 ml. of methyl alcohol are placed in a 100 ml. four-necked flask fitted with a stirrer, a dropping funnel, a reflux condenser and a thermometer. The solution is stirred and a mixture of 1.7 g. (0.044 mol) of sodium :borohydride in 4 ml. of water is added slowly through the dropping funnel at such a rate that the solvent refluxes gently without external heating. When the addition is complete and the initial reaction subsides, the mixture is stirred and heated at gentle reflux for six hours. The solvent is distilled oiT under reduced pressure and the residues is suspended in water and shaken with diethyl ether. The ether extract is dried over anhydrous magnesium sulphate, the solvent is removed by evaporation under reduced pressure and the oily residue is fractionated. Yield 4.9 g.; B.P. 120 C./0.4 mm. Hg.

By analogous procedures the following compounds have been prepared:

1- a-(N-benzyl -pyrryl] -2-diethylaminoetl1anol- B.P.=143-145 C./0.5 mm. Hg

1- u-(N-benzyl) -pyrryl] -2-dipropylaminoethano1- B.P.= 160-165 C./0.4 mm. Hg

1- u- (N-benzyl) -pyrryl] -2-diisopropylaminoethanol- B.P.=155-160 C./0.4 mm. Hg

1- [oc- (N-benzyl -pyrryl] -2-dibutylaminoethanol B.P.= 158-163 C./0.4 mm. Hg

1- a- (N-benzyl) -pyrryl] -2-disec. butylaminoethanol B.P.= 150-155 C./0.4 mm. Hg

1- a- (N-benzyl) -pyrryl -2-pyrrolidinoethanol B.P.= 148-153 C./0.4 mm. Hg

1- a- (N-benzyl -pyrryl] -2-piperidinoethanol M.P.=5052 C.

1- OL- (N-benzyl -pyrryl] -2-morpholinoethano1 M.P. =44-47 C.

1- [a- (N-benzyl -pyrryl] -2- (N-benzyl-N-methyl) aminoethanolB.P.= 195-200 C./0.2 mm. Hg

1- [a- (N-benzyl) -pyrryl] -2- (N'-benzyl-N'-tertbutyl aminoethanolM.P.= 123-125 C.

1- oc- (N-methyl) -pyrryl] -2-pyrrolidinoethanol-- M.P.=35-36 C.

1- oc- (N-methyl -pyrry1] -2-piperidinoethanol M.P.i=53-54 C.

1- [a- (N-phenyl -pyrryl] -2-diethylaminoethanol B.P.= 140-145 C./0.3 mm. Hg

1- a- (N-phenyl) -pyrryl -2-disec.butylaminoethan01- B.P.=135140 C./O.3 mm. Hg

1- vz- (N-benzyl) -pyrryl] -2-diiso.butylarnin0ethano1- B.P.=160-165 C./0.4 mm. Hg

1- a- (N-phenyl) -pyrryl] -2-pyrrolidinoethanol- B.P. =145-150 C./0.1-0.2 mm. Hg

1- [m- (N-phenyl) -pyrryl] -2-pyyrolidinoethanol hydrochlorideM.P.=119-121 C.

1-[a-(N-pheny1)-pyrryl]-2-piperidinoethanol B.P.=155160 C./0.1 mm. Hg

1- [a- (N-phenyl -pyrryl] -2-piperidinoethanol hydrochlorideM.P.= 140-142 C. (dec.)

1-[a-(N-o-chlorobenzyl)-pyrryl]-2-diethylaminoethanolB.P. 150-155 C./0.2 mm. Hg

1- a- (N-o-chlorobenzyl) -pyrryl] -2-disec.butylaminoethanolB.P=160-l 65 C./0.1 mm. Hg

1- oc- (N-o-chlorobenzyl) -pyrryl] -2-disec.buty1aminoethanol p-hydroxybenzoate-M.P.=128-13 C. (dec.)

1- [a- N-o-chlorobenzyl -pyrryl] -2-disec.buty1aminoethanol a-resorcylateM.P.=91-94 C. (dec.)

1- [0L- (N-o-chlorobenzyl) -pyrryl] -2-disec.-butylaminoethanol protocachuate-M.P. =60-70 C. (dec.)

1- [oc- (N-o-chlorobenzyl -pyrryl -2-pyrrolidinoethanol- B.P= 150-155 C./0.1 mm. Hg

1- [a- (N-o-chlorobenzyl) -pyrryl] -2-pyrrlodinoethanol hydrochlorideM.P.= 137-13 8 C.

1- u- (N-benzyl) -pyrryl] -2-diethylaminopropanol hydrochlorideM.P.= 140-142 C. (dec.)

1- a- (N-benzyl) -pyrryl] -2-p yrr0lidinopr0panol B.P.=-140 C./0.1-0.2 mm. Hg

1-[a-(N-benzyD-pyrryl]-2-pyrrolidinopropanol hydrochlorideM.P.= -142 C.

1- a- (N-benzyl) -pyrryl] -2-piperidinopropanol B.P=-l55 C./0.l-02 mm. Hg

1- a- (N-p-chlorobenzyl) -pyrryl] -2-diethy1aminoethanolB.P.= 160-165 C./0.1 mm. Hg

1- [a- (N-p-chlorobenzyl -pyrryl] -2-disec.butylaminoethanol-B.P.=160-l65 C./0.3 mm. Hg

1- oc- (N-p-chlorobenzyl pyrryl] -2-piperidinoethanol B.P.=-160 C./0.1 mm. Hg

loc- (N-p-chlorobenzyl) pyrryl] -2-piperidinoethanol hydrochlorideM.P.=134-135 C.

1- a- (N-p-chlorobenzyl) -pyrryl] -2-pyyrolidinoethano1-B.P. 145-155 C./0.1-O.2 mm. Hg

1- OC- N-p-chlorobenzyl -pyrryl] -2-pyyro1idinoethanol hydrochlorine-M.P.= 121-122 C.

1- cc- (N-o-chlorobenzyl) -pyrryl] -2-disec.butylaminoethanol -resorcylate-M.P.=72-74 C. (dec.)

1- a- (N-o-chlorobenzyl -pyrryl] -2-piperidinoethanol B.P.=140142 C./0.1 mm. Hg

1- oc- (N-o-chlorobenzyl -pyrryl] -2-piperidinoethanol hydrochlorideM.P.= 125-126 C.

1- oc- (N-ethyl) -pyrryl] -2-diethylaminoethanol- B.P.=94-96 C./0.4 mm. Hg

1- a- (N-benzyl) -pyrryl] -2- (N'-benzyl-N'-ethyl) aminoethanolB.P.= 195-200 C./0.2 mm. Hg

1- a- (N-ethyl) -pyrryl] -2-piperidinoethanol- B.P.=105-110 C./0.15 mm. Hg

loz- (N-ethyl) -pyrry1 -2-disec.butylaminoethanol B.P.= 100-105 C./0.2 mm. Hg

la- (N-methyl -pyrryl -2-diethylaminoethanol B.P.=90-95 C./0.3 mm. Hg

1- oc- (N-methyl -pyrryl] -2-diethylaminoethanol p.hydroxybenzo ate-M.P.= l 3 6-137 C./ (dec.)

1- a- (N-p-methoxybenzyl -pyrryl] -2-piperidinoethan0l-B.P.=175-185 C./0.3 mm. Hg

1- oc- (N-p-methoxybenzyl) -pyrryl] -2-piperidinoethanol oxalateM.P.=1 14-115 C. (dec.)

1- :x- (N-2.6-xylyl) -pyrry1] -2-pyrrolidinoethanol- B.P.= 150-160 C./0.2 mm. Hg

1- a- (N-2.6-xylyl -pyrryl] -2-pyrrolidinoethanol oxalateM.P.= 174-175 C.

1- a- (N-p-bromobenzyl -pyrryl] -2-pyrrolidinoethanol B.P.=-170 C./0.4 mm. Hg

1- [a- (N-p-bromobenzyl -pyrryl] -2-pyrrolidinoethanol picrateM.P.=13l-132 C.

1- a- N-2.6-xylyl) -pyrryl] -2-piperidinoethanol- B.P.= -170 C./2 mm. Hg

1- [a- (N-2.6-xylyl) -pyrryl] -2-piperidinoethanol oxalateM.P.= l63-l64 C. (dec.)

1- oc- (N-ethyl) -pyrryl] -2-pyrrolidinoethanol- B.P. =115-125 C./0.5 mm. Hg

1- vz- (N-ethyl -pyrryl] -2-pyrrolidinoethanol p-hydroxybenzoate-M.P.= 145-147 C. (dec.)

EXAMPLE II 10 g. (0.0278 mol) of l-(o-chloro)-benzyl-2-disec. butylaminoacetyl-pyrrole and 300 ml. of anhydrous diethyl ether are placed in a 500 ml. four necked flask with a mercury-sealed stirrer, a thermometer, a dropping funnel and a reflux condenser topped with a tube containing anhydrous calcium chloride. The solution is stirred and a mixture of 1 g. (0.0264 mol) of lithium aluminium hydride in 20 ml. of di-ethyl ether is added slowly through the dropping funnel at such a rate that the solvent refluxes gently without external heating. When the addition is complete and the initial reaction subsides, the mixture is stirred and heated at gentle reflux for two hours.

The mixture is cooled and the excess of lithium aluminum hydride is decomposed with cracked ice. The water layer is separated and washed with diethyl ether. The combined ether extracts are dried over anhydrous magnesium sulphate and the solvent is removed by distillation under reduced pressure. Yield, 8.8 g.; B.P.=160-165 C./ 0.1 mm. Hg.

An exemplary capsule suitable for oral administration has the following composition:

l-u-(N-o-chlorobenzyl)-pyrryl-Zdisecbutylaminoethanol p.hydroxybenzoate 41.5 Talcum 3 Dibasic calcium phosphate 63.5 Magnesium stearate 2 wherein R is selected from the group consisting of methyl, ethyl, phenyl and benzyl radicals which may contain one or two substituents selected from the group consisting of halogen, methyl and methoxy; R is alkyl with 1-4 carbon atoms; R is selected from the group consisting of alkyl with 1-4 carbon atoms and benzyl or taken together with R and the nitrogen atom to which they are attached isa heterocyclic ring selected from the group consisting of piperidinyl, pyrrolidinyl and morpholinyl; R is hydrogen or methyl; and its physiologically tolerable salts with organic acids, inorganic acids and alkyl halides.

2. 1- u- (N-o-chlorobenzyl -pyrryl] -2-disec.butylaminoethanol.

3. Physiologically tolerable salts with organic acids of 1 [oz (N o-chlorobenzyl)-pyrryl]-2-disec.butylamino ethanol.

4. Physiologically tolerable salts with inorganic acids of 1 [u-(N-o-chlorobenzyl)-pyrryl]-2-disec.butylamino ethanol.

References Cited Frizz Chemical Abstracts (1964), vol. 60, p. 6815 c. Wagner et al.: John Wiley, NY. (1953), pp. 149 and 152.

ALEX MAZEL, Primary Examiner B. I. DENTZ, Assistant Examiner US. Cl. X.R. 

